Method and apparatus to detect coronary artery calcification or disease

Abstract

Coronary artery calcification (CAC) occurs at an earlier age in diabetes and is a risk factor for coronary artery disease (CAD) in subjects with or without diabetes. One postulated mechanism for the increased CAC is the accelerated accumulation of advanced glycation end products (AGEs) in the vasculature. As certain collagen AGEs fluoresce, skin intrinsic fluorescence (SIF) can act as a novel maker of collagen AGEs levels. The present invention provides methods and apparatuses for detecting SIF that can be a useful marker of CAD risk and a therapeutic target.

1 . A method for determining the presence of coronary artery calcification in an individual, comprising:
 (a) providing a spectroscopic apparatus configured to measure the skin fluorescence of the individual;   (b) detecting the intrinsic skin fluorescence of the individual with the spectroscopic apparatus; and   (c) determining a measure of coronary artery calcification from the intrinsic fluorescence.   
     
     
         2 . A method as in  claim 1 , wherein the measure of coronary artery calcification is a quantitative measurement. 
     
     
         3 . A method as in  claim 1 , wherein the measure of coronary artery calcification is a qualitative measurement. 
     
     
         4 . A method as in  claim 1 , further comprising determining one or more additional factors concerning the individual, and wherein determining a measure of coronary artery calcification comprises determining a measure of coronary artery calcification from the intrinsic fluorescence and from the one or more additional factors. 
     
     
         5 . A method as in  claim 4 , wherein the one or more additional factors comprises one or more of the following: age of the subject, gender, ethnicity, current smoking status, previous smoking status, pack years smoking status, current smoking status times duration of smoking, renal function, estimated glomerular filtration rate, albumin excretion ratio, waist circumference, waist-to-hip ratio, BMI, systolic and/or diastolic blood pressure, use of blood pressure medication, diagnosis of hypertension, lipid levels, use of cholesterol medication, fasting glucose concentration, glycosylated hemoglobin concentration (HbA1c), casual glucose concentration, glucose concentration in response to a glucose challenge test, fructosamine, 1,5-anhydro-D-glucitol, c-reactive .protein, other markers of inflammation or markers of oxidative stress. 
     
     
         6 . A method of classifying an individual for risk of coronary artery calcification, coronary artery disease, or a combination thereof, comprising determining a measure of the skin intrinsic fluorescence of the individual, and classifying the individual risk from a model relating skin intrinsic fluorescence and risk. 
     
     
         7 . A method as in  claim 6 , further comprising determining one or more additional factors concerning the individual, and wherein classifying the individual risk from a model relating skin intrinsic fluorescence and risk comprises classifying the individual risk from a model relating (a) skin intrinsic fluorescence and the one or more other factors and (b) risk. 
     
     
         8 . A method as in  claim 7 , wherein the one or more additional factors comprises one or more of the following: age of the subject, gender, ethnicity, smoking status, previous smoking status, pack years smoking status, current smoking status times duration of smoking, renal function, estimated glomerular filtration rate, albumin excretion ratio, waist circumference, waist-to-hip ratio, BMI, systolic and/or diastolic blood pressure, use of blood pressure medication, diagnosis of hypertension, lipid levels, use of cholesterol medication, fasting glucose concentration, glycosylated hemoglobin concentration (HbA1c), casual glucose concentration, glucose concentration in response to a glucose challenge test, fructosamine, 1,5-anhydro-D-glucitol, c-reactive protein, other markers of inflammation or markers of oxidative stress. 
     
     
         9 . A method as in  claim 1 , wherein the spectroscopic apparatus comprises:
 (a) an illumination system adapted to produce light at a plurality of broadband wavelength ranges;   (b) an optical probe adapted to receive broadband light from the illumination system and transmit the broadband light to in vivo tissue, and to receive light diffusely reflected in response to the broadband light, emitted from the in vivo tissue by fluorescence thereof in response to the broadband light, or a combination thereof;   (c) a calibration device which can be periodically placed in optical communication with the optical probe;   (d) a spectrograph adapted to receive the light from the optical probe and produce a signal representative of spectral properties of the light; and   (e) an analysis system adapted to determine a property of the in vivo tissue from the spectral properties signal.   
     
     
         10 . The method of  claim 9 , wherein the calibration device comprises a fluorescent material. 
     
     
         11 . The method of  claim 10 , wherein the calibration device substantially blocks ambient light from reaching the optical probe when the calibration device is placed in optical communication with the optical probe. 
     
     
         12 . The method of  claim 10 , wherein the calibration device comprises a reflective material. 
     
     
         13 . The method of  claim 10 , wherein the calibration device comprises a housing that defines a chamber having walls, a fluorescent material disposed on at least a portion of the walls, a reflective material disposed on at least a portion of the walls, wherein the housing has a first end adapted to substantially prevent ambient light from reaching the optical probe when the chamber if placed in optical communication with the optical probe. 
     
     
         14 . The method of  claim 13 , wherein the chamber has a substantially spherical shape. 
     
     
         15 . The method of  claim 13 , wherein the chamber has a cross-section that provides uniform illumination of the optical probe with light reflected by the calibration device as well as fluorescence emitted by the calibration device. 
     
     
         16 . The method of  claim 9 , wherein the spectroscopic apparatus further comprises an operator display adapted to communicate information concerning the determined tissue property, where the display mounts with the apparatus such that the display can be adjusted in two angular dimensions, and wherein the operator display comprises a touchscreen adapted to accept input from an operator responsive to touch of the screen by the operator. 
     
     
         17 . The method of  claim 16 , wherein the display can be adjusted such that a human whose tissue is being sampled by the apparatus cannot see the display. 
     
     
         18 . The method of  claim 9 , wherein the spectroscopic apparatus further comprises an arm positioning element adapted to position a human arm relative to the optical probe such that the optical probe communicates light with a portion of the forearm, and wherein the arm positioning element has a concave shape that interfaces the forearm with the optical probe in a manner that substantially prevents ambient light from being detected by the optical probe. 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 9 , wherein the spectrograph is adapted to produce a spectrum that is substantially free of ghost images and stray light. 
     
     
         22 . The method of  claim 21 , wherein the spectrograph comprises a back-illuminated CCD image sensor. 
     
     
         23 . The method of  claim 22 , wherein the back-illuminated CCD is oriented non-perpendicular to the axis of incident light thereon. 
     
     
         24 . The method of  claim 9 , wherein the spectrograph comprises an out-of-plane Littrow spectrograph. 
     
     
         25 . The method of  claim 21 , wherein spectrograph comprises a front-illuminated CCD detection element. 
     
     
         26 . (canceled) 
     
     
         27 . A method of determining the CAC value of a subject, or detecting whether a subject has a clinically significant CAC above a predetermined threshold, comprising:
 determining the intrinsic fluorescence of a portion of the skin of the subject;   determining the CAC value of a subject, or detecting whether a subject has a clinically significant CAC above a predetermined threshold, from the intrinsic fluorescence.   
     
     
         28 . A method as in  claim 27 , wherein determining the intrinsic fluorescence comprises determining the sum of intrinsic fluorescence of the skin at each of a plurality of wavelengths. 
     
     
         29 . A method as in  claim 28 , wherein the step of determining the CAC value, or detecting a clinically significant CAC, comprises using a multivariate model that relates CAC to the sum of intrinsic fluorescence and one or more of the following: age of the subject, gender, ethnicity, diagnosed type 1 or type 2 diabetes, skin tone, skin tone quantified by the sum of the skin reflectance across the fluorescence emission band, current smoking status, previous smoking status, pack years smoking status, current smoke smoking status times duration of smoking, renal function, estimated glomerular filtration rate, albumin excretion ratio, waist circumference, waist-to-hip ratio, BMI, systolic and/or diastolic blood pressure, use of blood pressure medication, diagnosis of hypertension, lipid levels, use of cholesterol medication, fasting glucose concentration, glycosylated hemoglobin concentration (HbA1c), casual glucose concentration, glucose concentration in response to a glucose challenge test, fructosamine, 1,5-anhydro-D-glucitol, c-reactive protein, other markers of inflammation or markers of oxidative stress. 
     
     
         30 . (canceled) 
     
     
         31 . A method as in  claim 29 , wherein the multivariate model accepts as input an information vector comprising intrinsic fluorescence and one or more of the following: age of the subject, gender, ethnicity, diagnosed type 1 or type 2 diabetes, skin tone as quantified by the sum of the skin reflectance across the fluorescence emission band, current smoking status, previous smoking status, pack years smoking status, current smoking status times duration of smoking, renal function, estimated glomerular filtration rate, albumin excretion ratio, waist circumference, waist-to-hip ratio, BMI, systolic and/or diastolic blood pressure, use of blood pressure medication, diagnosis of hypertension, lipid levels, use of cholesterol medication, fasting glucose concentration, glycosylated hemoglobin concentration (HbA1c), casual glucose concentration, glucose concentration in response to a glucose challenge test, fructosamine, 1,5-anhydro-D-glucitol, c-reactive protein, other markers of inflammation or markers of oxidative stress. 
     
     
         32 . (canceled) 
     
     
         33 . A method as in  claim 27 , wherein using a multivariate model comprises selecting a multivariate model from a plurality of multivariate models based on one or more of the following: the subject's gender, the subject's age, the subject's ethnicity, or the subject's skintone. 
     
     
         34 . A method as in  claim 27 , wherein using a multivariate model comprises combining the outputs of a plurality of multivariate models. 
     
     
         35 . (canceled) 
     
     
         36 . (canceled)